Schizophrenia continues to be a major public health problem. Clinical symptoms resembling those exhibited by schizophrenic patients are manifested by individuals who ingest large doses of amphetamine and its congeners. In this proposal the schizophrenic-like condition that occurs in humans who take amphetamines in large doses will be simulated in rats. We have observed previously that haloperidol, given concurrently, will prevent the methamphetamine-induced changes in a 5-hydroxytryptamine (5HT) and dopamine (DA) metabolism. We now wish to simulate more closely the patient who is diagnosed as having schizophrenia, and is then administered neuroleptic drugs. In preliminary studies we have demonstrated that haloperidol not only prevented but more importantly can reverse the methamphetamine-induced alternation in 5HT and DA metabolism. This experiment is more analogous to the patient who develops schizophrenia and is subsequently treated with an antipsychotic drug. Rats will be administered large doses of methamphetamine and tryptophan hydroxylase activity, as well as concentrations of 5-hydroxytryptamine (5HT) and 5-hydroxyindoleacetic acid (5HIAA), will be measured in different brain regions. Concurrent analysis of dopamine synthesis and metabolism will also be performed. In parallel experiments, haloperidol will be administered to saline-treated and methamphetamine-treated rats. Dose- and time-response relationships of the effects of haloperidol will be constructed. Other antipsychotic drugs will then be tested and their ability to reverse the methamphetamine-induced neurochemical changes will be compared to their clinical efficacy. The enzymatic activities will be measured by radioenzymatic procedures. Concentrations of neurotransmitters and their metabolites will be measured by high performance liquid chromatography with electrochemical detection (HPLC-EC). These studies will provide information that will hopefully have application in understanding the neurochemical alterations which occur in schizophrenia and other related mental illnesses. The findings will also reveal information that is pertinent to understanding normal function in the brain regions analyzed.